Roles of p53-Regulated Pro-Survival Signals in Carcinogenesis by HTLV-1 and High-Risk Subtype HPVs - The human T-cell leukemia virus type-1 (HTLV-1) is a delta oncoretrovirus that infects and transforms
CD4+ T-cells and causes adult T-cell leukemia/lymphoma (ATLL), an aggressive hematological
malignancy that is generally resistant to conventional anticancer therapies. The 3' end of the HTLV-1
genome encodes several regulatory proteins (i.e., Tax, Rex, HBZ, p8I, p12I, p13II, and p30II) from a highly-
conserved nucleotide sequence, known as pX, which is retained in the majority of ATLL clinical isolates.
For nearly four decades, the HTLV-1 has been extensively studied as a general informative model for
viral carcinogenesis; however, to date, none of its products have been shown to contain structural or
functional similarities to other oncogenic viruses beyond the primate T-cell lymphotropic virus (PTLV)
family. My laboratory has identified a core structural domain within the HTLV-1 p30II protein with
homology to the E6 oncoproteins of high-risk subtype human papillomaviruses (hrHPVs). Both HTLV-1
p30II and HPV E6 cooperate with the cellular oncoprotein, c-Myc, and prevent p53-dependent apoptosis
by inhibiting TIP60-mediated acetylation of the p53 protein on lysine residue K120. Intriguingly, p53 is
rarely mutated in HTLV-1+ ATLL and HPV+ cervical cancer clinical isolates –although E6 degrades the
p53 protein and significantly reduces its expression through interactions with the ubiquitin ligase, E6AP.
Our preliminary studies have demonstrated that the HTLV-1 p30II and HPV16/18 E6 viral oncoproteins
induce the expression and mitochondrial localization of the TP53-induced glycolysis and apoptosis
regulator (TIGAR) and p53-inducible ribonucleotide reductase (p53R2). Primary patient-derived ATLL
and HPV+ cervical carcinoma samples contain elevated levels of TIGAR and p53R2 that correlate with
oncogenic c-Myc expression. We have further shown that lentiviral-siRNA-knockdown of TIGAR inhibits
in vivo tumorigenesis and metastatic disease progression in xenograft models of HTLV-1-induced T-cell
lymphoma and HPV-induced squamous cell carcinoma. Based upon these findings, we hypothesize that
the unrelated HTLV-1 and high-risk subtype HPVs may have evolved similar strategies to deregulate
host oncogenic and pro-survival signaling pathways by targeting p53 functions. The following Specific
Aims are proposed for this R15 AREA project: 1) to elucidate the molecular mechanisms by which the
HTLV-1 p30II and high-risk HPV E6 oncoproteins modulate p53-regulated pro-survival signals, 2) to
determine how TIGAR and p53R2 contribute to the cooperation between HTLV-1 p30II or hrHPV E6
oncoproteins and cellular oncogenes, and 3) to elucidate the roles of these p53-regulated pro-survival
signals in HTLV-1 and HPV-induced tumorigenesis in vivo. The proposed studies will yield valuable new
insight into the evolutionary relationship between HTLV-1 and other cancer-inducing viruses and advance
our understanding of the roles of p53-regulated pro-survival signals in viral carcinogenesis.
